Involvement of endocannabinoid receptor 1 in oxidative and inflammatory responses underlying anxiety-like behavior in SPS&S-exposed mice.

OBJECTIVE

This study investigated the role of endocannabinoid (eCB) signaling in anxiety-like behaviors associated with a PTSD mouse model (SPS&S), focusing on oxidative stress and inflammation.

METHODS

We examined expression of eCB-related proteins (Cannabinoid receptor type 1, CB1 Receptor; NAPE-specific phospholipase D, NAPE-PLD; Fatty acid amide hydrolase, FAAH; and Monoacylglycerol lipase, MAGL) and inflammatory markers (IL-1β, caspase-1) in the mPFC, hippocampus, and amygdala of SPS&S-exposed mice. Plasma oxidative stress markers (MDA, SOD, ROS) and cytokines (IL-1β, IL-6, TNF-α, COX-2) were measured by ELISA. The CB1 receptor agonist WIN 55,212-2 or vehicle was administered systemically, then anxiety-like behaviors and conditioned fear were assessed.

RESULTS

SPS&S exposure induced significant anxiety-like behaviors and increased freezing in fear tests. It decreased CB1 receptor and NAPE-PLD expression while increasing FAAH and MAGL levels in all examined brain regions, alongside elevated IL-1β and caspase-1. Plasma oxidative stress and inflammatory cytokines were also elevated. WIN 55,212-2 administration mitigated anxiety-like behaviors but not conditioned fear responses. Crucially, it normalized the elevated plasma oxidative stress and inflammatory cytokine levels.

CONCLUSION

SPS&S disrupts eCB signaling and increases neuroinflammation and peripheral oxidative stress/inflammation. Activation of CB1 receptor alleviates PTSD-associated anxiety-like behaviors and normalizes peripheral oxidative/inflammatory biomarkers, highlighting the critical involvement of eCB-related oxidative stress and inflammatory pathways. Targeting the eCB system represents a potential therapeutic strategy for anxiety symptoms in PTSD.